Alzheimer Disease (AD) plagues our ageing population as the most common cause of cognitive impairment in the elderly and the sixth leading cause of death in America. AD is characterized by progressive dementia and the presence of beta-amyloid (A-beta) plaques, neurofibrillary tangles, and enlarged endosomes in the brain. Interestingly, Down Syndrome (DS) patients over the age of 35 invariably develop AD-like neuropathology, suggesting that this variant of AD is caused by trisomy of genes related to AD on chromosome 21. The core of AD pathology is attributed to aberrant processing of Amyloid Precursor Protein (APP), which is encoded on chromosome 21. APP triplication produces a partial AD phenotype, but is not sufficient to produce the full spectrum of cognitive symptoms and neuropathologic signs that define AD. In contrast, partial trisomy 21 spanning the DS critical region (DSCR) is sufficient to produce AD in DS patients. These data suggest that other DSCR genes are required, in addition to APP, for the development of AD. The fact that the scaffold protein Intersectin1 is located on the DSCR, overexpressed at the mRNA and protein level in DS, and differentially expressed in the brains of DS patients with and without a diagnosis of AD makes ITSN1 a strong candidate. This hypothesis is strengthened by ITSN's ability to enhance neurodegeneration and function in multiple pathways that promote pathogenic APP processing in AD. ITSN1 regulates two major processes that are deranged in AD: endocytosis and the c-Jun-N-terminal kinase (JNK) activation. ITSN1 regulates multiple aspects of endocytosis that are critical for the internalization of APP and its subsequent processing. ITSN also activates JNK and JNK activation further contributes to pathogenic APP processing and neurodegeneration. Thus, in DS and AD the overexpression of ITSN1 may result in increased APP endocytosis and JNK activation, thereby increasing the production of neurotoxic APP cleavage products. This research will (1) determine the effect of modulating ITSN1 levels on APP processing, (2) determine the role of ITSN1-regulated pathways, such as endocytosis and JNK signaling, in APP processing, and (3) determine the contribution of ITSN1 to in vivo processing of APP & amyloid plaque formation using novel transgenic mice. As the first study to investigate the role of ITSN1 in AD, these experiments will provide novel insight into the early endocytic pathology and regulation of APP processing. The unique approach of this application links the subclinical endocytic and amyloidogenic anomalies observed in AD and DS and offers the possibility of new biomarkers and therapeutic targets that precede the cognitive manifestations and classic histopathology of AD. PUBLIC HEALTH RELEVANCE: Endocytic abnormalities are now recognized as the earliest manifestation of Alzheimer Disease, preceding the development of cognitive symptoms. Our work investigates the role of a scaffold protein, intersectin1, in the etiology of this preclinical pathology. Understanding the role of intersectin1-regulated pathways in this disease process will aid in the potential development of preventative and therapeutic technologies.